Agonist-anatagonist combination to reduce the use of nicotine and other drugs

ABSTRACT

A method of treating and reducing a drug dependency such as a nicotine dependency is provided. The method comprises initially administering to a subject a drug, such as nicotine or another agonist of the drug in an amount which would normally provide the desired pharmacologic effects and at least partially satiate the needs for the drug by a user. The method also comprises administering to the subject an antagonist to the drug or its other agonist in an amount sufficient to at least partially block the pharmacologic defects of the drug or its other agonist while there is a substantial amount of the drug or other agonist present in the system of the user. In one embodiment of the invention, the drug and the antagonist are administered substantially simultaneously so as to occupy a substantial portion of the receptors of the user for that drug thereby blocking or attenuating the effects of any further intake of the drug or other agonist. In another embodiment, the drug or its other agonist is first administered and the antagonist is self-administered by a subject in a manner which mimics the use of the drug thereby counter-conditioning the drug user to the stimuli associated with the normal administration of the drug. The invention further provides a method of therapeutically treating psychophysiologic diseases and disorders involving neuronal dysregulation. The method additionally provides a pharmacologic composition for the treatment and reduction of drug dependence and which relies upon a combination of an agonist and antagonist.

GOVERNMENT RIGHTS

This invention was made with the support of the Veterans Administrationof the United States government. The government has certain rights inthis invention.

RELATED APPLICATION

This application is a continuation of our application Ser. No.08/570,530 filed Dec. 1, 1995 now U.S. Pat. No. 5,703,101 for"Agonist-Antagonist combination to Reduce the Use of Nicotine and OtherDrugs" which is a continuation of our U.S. patent application Ser. No.08/235,454, filed Apr. 29, 1994 now U.S. Pat. No. 5,574,052 for"Agonist-Antagonist Combination To Reduce The Use Of Nicotine And OtherDrugs", which is a continuation of our U.S. patent application Ser. No.08/054,144, filed Apr. 30, 1993, for "Agonist-Antagonist Combination ToReduce The Use Of Nicotine And Other Drugs" (now abandoned), which was acontinuation of our U.S. patent application Ser. No. 07/855,868, filedMar. 23, 1992 now U.S. Pat. No. 5,316,759 for "Agonist-AntagonistCombination To Reduce The Use Of Nicotine And Other Drugs", which was acontinuation of our U.S. patent application Ser. No. 07/231,092, filedAug. 11, 1988, now abandoned for "Agonist-Antagonist Combination ToReduce The Use Of Nicotine And Other Drugs", (now abandoned) which is acontinuation-in-part of patent application Ser. No. 840,072, filed Mar.17, 1986, entitled "Smoking of Regenerated Tobacco Smoke" (now U.S. Pat.No. 4,846,199, dated Jul. 11, 1989).

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates in general to certain new and useful improvementsin methods and compositions for treating and reducing drug dependencyand for therapeutically treating psychophysiologic diseases anddisorders involving neuronal dysregulation and more particularly, tomethods and compositions of the type stated which rely upon theadministration of a combination of a drug or another agonist and anantagonist to the drug.

2. Brief Description of the Prior Art

The substantial use of drugs and particularly, the widespread abuse ofdrugs has led to increased incidence of health problems and has evenlargely contributed to significant increases in crime. It has been wellestablished that the intake of the drug nicotine through tobacco smokinghas resulted in various adverse health conditions. While the use ofdrugs, such as nicotine, do not necessarily lead to increased incidenceof crime, use of this drug and similar related drugs does presentsignificant health problems.

While the use of other addictive drugs including controlled substancessuch as various narcotics, e.g., heroin and cocaine, also can result inadverse health conditions, these more serious drug uses have asignificant social impact in that they give rise to a substantialincrease in numerous types of criminal activity. Various governmentalagencies have expended substantial sums of money in attempting toeradicate or at least reduce the incidence of crime, but without muchsuccess. Accordingly, in recent years, there has been an increasedemphasis on attempting to treat and reduce drug dependency.

The use of drugs is also involved in the treatment of variouspsychophysiologic disorders, and particularly psychiatric disordersinvolving dysregulation of a neurotransmitter. In addition, certaindiseases involving imbalances of the autonomic nervous system aretreated by administration of certain drugs. Here again, these drugs mayhave serious side effects in that while they may attenuate a certaindisorder, they exacerbate other disorders. Further, many of the drugsused to treat these disorders can produce dependence as for example adependence on diazepam (Valium). Therefore, the subject, while findingsome release from the disorder or disease, may become severely addictedto the drug which is used.

In general, two approaches have been used in the pharmacologic treatmentof drug dependence. The first approach is often described as the"substitution approach" and provides an alternative drug which isdesigned to theoretically allow the user to withdraw from the habituallyabused drug without suffering the aversive symptoms normally associatedwith a withdrawal from a drug. As a simple example, methadone is oftenadministered to heroin addicts in the treatment of heroin addiction. Itwas anticipated and initially believed that a substitution of methadonefor heroin, for example, would lead to the eventual cessation of alldrug use after a weaning period in which the dose of the substituteddrug was gradually reduced.

This first approach to drug dependency has met a very low rate ofsuccess. It has been found that the substitution of one drug for anotherdoes not typically wean the subjects from all drugs. In fact, it hasbeen found in many cases that the drug users will store the substituteddrug, such as the methadone, and continue to use the more addictivedrug, heroin or morphine, and only use the stored substitute, methadone,when the heroin or morphine is not readily available. Thus, this firstapproach to reduced drug dependency has met with very little success.

There have also been various proposed treatments for the administrationof nicotine (the putative addictive substance in tobacco smoking) as areplacement for tobacco smoking. One of the most successful approacheswhich have been used to date in reducing the incidence of tobaccosmoking relies upon nicotine containing chewing gum. The use of thistype of gum suffers from several problems, including not only the badtaste and destruction of dental appliances, but the gastrointestinalupset which results therefrom and which also reduces compliance.Moreover, the nicotine containing chewing gums do not satisfy thatcraving which most smokers experience for the distinct sensations in thethroat and chest elicited by the nicotine in smoke. Over the course ofmany years of tobacco smoking, these particular sensations have becomean important part of and conditioned with the habit of smoking and helpmaintain tobacco smoke dependency.

There have also been several proposals for administering nicotinethrough various aerosol sprays. However, the aerosol sprays are designedto supply that amount of nicotine which would have been acquired by auser through the normal channel of tobacco smoking. The sprays result insevere respiratory tract irritation. There is no available means toprovide the nicotine either by means of an oral or nasal spray andattenuate the severe irritating effects of the nicotine.

The second known general approach which has been used in thepharmacologic treatment of drug dependence involves the blocking of thereinforcing effects of the abused drug. It is theorized that by reducingthe motivation of the user, there would be a reduced incidence ofself-administration of a drug by the user. As a simple example,naltrexone is presently used to block the reinforcing effects of heroinand mecamylamine has been used to block the reinforcing effects ofnicotine. This latter approach has not been found to be effective inthat the intense withdrawal symptoms suffered by the user encouragecompensating use of the addictive drug and thereby reduce compliancewith the treatment unless a sufficient period of abstinence has elapsedso that the individual's nervous system is accustomed to the absence ofthe abused drug. The administration of an antagonist alone also createsa dysphoric state which encourages relapse and return to the abuseddrug.

Each of the aforementioned approaches have only been usedexperimentally. Moreover the individual antagonist approach and theindividual agonist approach have each been found to be relativelyineffective. The second approach has been ineffective due to the factthat there are significant withdrawal or other adverse symptoms. Thiscauses the drug abuser to return to his original drug habit in order toavoid the pain and discomfort associated with the withdrawal. Thus, thislatter approach to reduce drug dependency has also met with littlesuccess.

Heretofore, no one has attempted to combine the sustained administrationof a drug agonist and an antagonist to that drug in a therapeutictreatment. It would appear that the administration of an agonist and itsantagonist would accomplish little, since the antagonist wouldeffectively cancel out the effects of the agonist with a result that thecombination would be equivalent to giving nothing at all.

OBJECTS OF THE INVENTION

It is, therefore, one of the primary objects of the present invention toprovide a method of reducing the dependency on drugs by utilizing acombination of an agonist and an antagonist.

It is another object of the present invention to provide a method of thetype stated for reducing drug dependency by simultaneously administeringa drug or another agonist of that drug along with an antagonist to thatdrug and thereby occupy a substantial number of the receptors of asubject available to that drug or its agonist.

It is a further object of the present invention to provide a method ofthe type stated which enables administering an agonist and antagonistwithout causing an over-activity or under-activity of the receptor forthe agonist thereby avoiding dangerous side effects which would occur ifthe agonist or antagonist were given alone in the same dosages.

It is a another salient object of the present invention to provide amethod of the type stated in which a drug or another agonist of thatdrug is administered to an individual to provide a certain systemiclevel and an antagonist is self-administered by the individual whichcauses a reduction in the satisfaction associated with the intake of thedrug or its other agonist.

It is also an object of the present invention to provide a method fortreating psychophysiologic disorders and diseases involving neuronaldysregulation by the simultaneous application of an agonist and anantagonist in relative amounts so that substantial portions are presentin the bloodstream in the patient having the disorder or disease.

It is an additional object of the present invention to provide a novelcomposition of a drug or another agonist of that drug and an antagonistto that drug.

With the above and other objects in view, our invention resides in thenovel features of form and arrangement and combination of steps in themethod and in the components forming part of the composition ashereinafter described.

BRIEF SUMMARY OF THE INVENTION

The present invention relates in general terms to a method of treatingand reducing drug dependency. Any of a number of known drug dependenciescan be treated in accordance with the method of the invention includingfor example, dependency on nicotine, heroin (or morphine) cocainebenzodiazepines, and the like. The invention in a broad aspect reliesupon a combination of an administration of a drug or another agonist ofthe drug and an antagonist to the drug. The present invention alsoprovides a unique method of therapeutically treating psychophysiologicdiseases and disorders involving neuronal dysregulation by asimultaneous administration of a drug or another agonist of the drug andan antagonist to the drug.

The term "agonist" is used in a broad sense and includes the drug ofinterest. Thus, for example, in this case, nicotine is an agonist andheroin is an agonist. Methadone is merely another agonist for heroinsince it provides effects similar to that of heroin. Thus the term"agonist" as used herein, unless otherwise specified, will include thedrug itself.

The method in a broad sense, comprises initially administering to asubject a drug or another agonist of this drug in an amount which wouldnormally provide the desired pharmacologic effects. Moreover, the amountof the drug applied would at least partially satiate the needs for thedrug by the user. The method also involves the administering to asubject an antagonist to the drug or its other agonist in an amountsufficient to at least partially block the pharmacologic effects of thedrug or its other agonist while there is a substantial systemic amountof the drug or its agonist present.

The method of the present invention involves two general approaches tothe treatment of drug dependency and to the therapeutic treatment of theabove described psychophysiologic diseases and disorders which involveuse of drugs. In the first approach, there is a treatment for thedependency on the drug by saturating a substantial portion of the knownreceptors for that drug with a combination of the drug or its otheragonist and an antagonist to that drug or such other agonist. In thiscase, the agonist or drug is administered in an amount to which thesubject is generally dependent upon that drug to thereby satisfy ademand for the drug. The antagonist is generally simultaneouslyadministered to the same subject in an amount to attenuate thepharmacologic effects of the drug or its other agonist. In this case,the drug or its other agonist and the antagonist are preferably presentin such an amount that more receptors of the drug are occupied by thedrug and the antagonist than could safely be occupied by the drug aloneor the antagonist alone. Moreover, a lesser number of the receptors areleft available to respond to the drug thereby insulating the user fromthe reinforcing effects of the drug and at the same time minimizingadverse symptoms associated with the antagonist. With the use of thecurrent agonist-antagonist therapy one can attenuate the fluctuations ofa neural system while keeping the absolute level of activation constant.In other words, one can attenuate the impact of an abused drug withoutcausing a withdrawal syndrome and one can decrease the pathologicallywide fluctuations in neural activity without adverse side effectsassociated with giving only an agonist.

In this case, the purpose of the invention is to saturate the receptorsof the drug to thereby insulate the individual from the reinforcingeffects of the drug. In the case of nicotine, the individual would beadministered both nicotine and an antagonist to nicotine, such asmecamylamine. In the case of other drugs such as heroin, or its agonist,methadone, the antagonist naltrexone would be administered.

In accordance with this aspect of the invention, the drug may be presentin an amount which would otherwise be toxic in the absence of theantagonist but the toxicity is offset by the presence of the antagonist.The drug should preferably be administered in a sufficiently high doseto occupy a sufficient number of the receptors and thereby substantiallyreduce a subject's demand for the drug.

In one preferred embodiment, both the drug, or its other agonist, andthe antagonist may be administered by means of a transdermal patch, ashereinafter described in more detail. The drug or its other agonist andfor that matter the antagonist, may be administered by other means suchas oral administration, intravenous administration etc. In order to weanthe person from the use of the drug, both the drug, or its otheragonist, and the antagonist may be reduced in selected amounts over aperiod of time.

The use of this approach is effective in that the user will receivelittle or no satisfaction from taking additional amounts of the druginasmuch as a very substantial portion of the receptors for that drugare already occupied by the initial dose of the drug and the initialdose of the antagonist to the drug.

The second general approach used in the administration of the agonistand an antagonist involves an inverse conditioning to the stimuliassociated with the taking of the abused drug. In this case, the methodinvolves the administering to a subject a drug or another agonist of thedrug in an amount which would achieve a systemic level of the drug towhich the subject was previously accustomed. This approach to the methodalso involves the self-administration of an antagonist to the drug orits other agonist, but only at selected intervals. Moreover, theantagonist is preferably administered in a form similar to theadministration of the abused drug, as hereinafter described.

While this approach does increase the saturation of the receptors forthe drug by the presence of the drug and the antagonist, it moreimportantly causes a reduction of the enjoyable effects associated withthe taking of the drug. The subject is administered a certain amount ofthe drug or other agonist to provide a desired systemic level. Theadministration of the antagonist is preferably in a form with sensorycues which mimics or closely simulates the form in which the user wasaccustomed to taking the drug, as aforesaid. Thus, by taking the drug inthis form, there is an inverse conditioning or counter-conditioning ofthe stimuli associated with the taking of the drug.

As a simple example of this latter approach in treating and reducingdrug dependency, the dependency on nicotine could be reduced byproviding a desired systemic level of the nicotine through a transdermalpatch or other means. The antagonist, such as mecamylamine, could beincorporated into a smoking device, such as a simulated cigarette whichprovides many if not most of the sensory cues in normal tobacco smoking.In this way, when the user took a puff from the simulated cigarette,instead of receiving nicotine, he would receive an antagonist, namelythe mecamylamine, thereby further depriving the user of thepharmacologic effects of nicotine to which he or she was previouslyaccustomed. The usual conditioning is that smoking is associated withincreased nicotine stimulation and pleasurable effects. However, in thiscase, smoking and its attendant sensory cues would be associated withdecreased nicotine stimulation and the unpleasant effects of withdrawalwhenever the user smoked.

It can be observed that one important factor in each of the aboveidentified approaches to the method of the present invention is thatthere is generally a sustained level of the agonist in a user'sbloodstream. When using the first approach, there would generally be asustained level of both the agonist and the antagonist since they aregenerally simultaneously administered. In the second approach, therewould at least be the sustained level of the agonist and the user wouldself-administer the antagonist at the will of the user. Thus, therewould be peaks in the amount of the antagonist in the bloodstream of theuser of the second approach.

Preferably, in both approaches to the method of the invention, theagonist is administered by a route which is different than that employedin the actual use of the drug. Thus, in the case of nicotine,administration of an agonist would occur by means of a transdermal patchor a route other than by way of smoking. In the case of the heroin,methadone would likely be used because it has a longer acting effectthan heroin, but would be administered by a route different than theuser employed for the administration of heroin. Thus, if the userself-administered heroin through a hypodermic needle, the methadonewould be administered orally or by means other than a hypodermic needle.In this way, there will not be any reinforcement of the originalresponse obtained by the common method of using the drug.

In both approaches, it can also be observed that there is essentially noself-administration of the agonist alone. In other words, the agonistmay be self-administered in combination with the antagonist as forexample, a composition in the form of a pill or tablet. Otherwise, theagonist would generally always be administered in a therapy, as forexample, in a treatment center, or the like. The antagonist could beself-administered, as described above.

The present invention is also highly effective in the treatment ofvarious psychophysologic disorders and diseases involving neuronaldysfunction, as described above. The invention utilizing both theagonist and the antagonist is effective in treating disorders involvingdysregulation of a neurotransmitter as for example, in manic depressionand schizophrenia. Imbalances of the autonomic nervous system can alsobe treated by the concurrent agonist-antagonist administration, as well.In particular, sympathetic nervous system disorders e.g. hypertensioncould also be treated by this approach with the adrenergicagonist-antagonist combinations.

The present invention also provides a unique composition of both anagonist and an antagonist. The composition is novel and unobvious inview of the fact that one would not normally attempt to combine anagonist and an antagonist for the reasons described above. Moreover, itis important to have a single composition which may be in tablet or pillform, for example, or which may be administered through a transdermalpatch. In this way, the user who is typically an abuser of a drug oranother agonist of that drug will not be able to separate the desiredportion of the composition, namely the drug or agonist from theantagonist. When the user takes the composition, the user will receiveboth the drug or its other agonist and the antagonist to the drug.

This invention possesses many other advantages and has other purposeswhich will be made more clearly apparent from a consideration of theforms in which it may be embodied. They will now be described in moredetail for purposes of illustrating the general principles of theinvention, but it is to be understood that such detailed description isnot to be taken in a limiting sense.

BRIEF DESCRIPTION OF THE DRAWINGS

Having thus described the invention in general terms, reference will nowbe made to the accompanying drawings (two sheets) in which:

FIG. 1 is a somewhat schematic vertical sectional view of a transdermalpatch for the transdermal administration of an agonist or an antagonist;

FIG. 2 is a vertical sectional view of an apparatus capable of beingused for inhaling an aerosol of an agonist or an antagonist;

FIG. 3 is a schematic side elevational view, partially broken away andin section, and showing a modified form of apparatus for inhaling anaerosol of an agonist or an antagonist;

FIG. 4 is a schematic side elevational view, partially broken away andin section, and showing another modified form of apparatus for inhalingan aerosol of an agonist or an antagonist;

FIG. 5 is a fragmentary sectional view taken along line 5--5 of FIG. 4;

FIG. 6 is a graph showing a normal conditioning of a smoker withnicotine receptor activation as a function of time; and

FIG. 7 is a graph showing an inverse conditioning of smokers withnicotine receptor activation as a function of time.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Referring now in more detail and by reference characters to thedrawings, which illustrate several practical embodiments of the presentinvention, the invention relies in its principle aspect, upon theadministration of a drug, or another agonist of the drug, and anantagonist to the drug, as previously described. As also indicatedabove, there are two major approaches to reduction of drug dependencyusing a combination of the agonist and an antagonist.

In the first of these approaches, an effective treatment strategy isbased upon the combined administration of the agonist and an antagonist.The net result of the administration of the drug, or another agonist ofthat drug and its own antagonist is that even more receptors of theusers brain for that drug are occupied than if either the agonist or theantagonist were given alone. As a result, the drug user is furtherinsulated from any reinforcing effects of the abused substances. As anexample, by administering a dose of nicotine and dose of mecamylamine,the user is insulated from the formerly desirable effects associatedwith the smoking of tobacco and which desired effects were primarly theobtaining of nicotine. Few receptors are left available to respond tothe abused substance in this case because the receptor system is atleast partially saturated.

It should be understood that the receptor system could only be partiallysaturated in that there could be serious adverse consequences to thepatient or other subject if all of the receptors were occupied by eithera drug or an agonist. Nevertheless, in the context of the presentinvention, a much larger number of receptors are occupied than wouldotherwise be occupied if the subject was receiving only a drug or otheragonist and the antagonist.

A further advantage of this approach over the administration of anagonist alone, or an antagonist alone, is that the toxic effects ofeither drug are offset by the other. As a simple example, in the case ofnicotine, it may not be safe to administer a sufficiently high dose ofthe nicotine to occupy enough receptors for obtaining a maximalsuppression of an individual's craving for cigarettes. However, byconcurrently administering an antagonist for the nicotine, such asmecamylamine, a higher dose of the nicotine could be administered. Inlike manner, it is possible to deliver a higher dose of a highlyaddictive drug, such as heroin or morphine, when naltrexone isadministered.

The agonist and the antagonist are preferably simultaneouslyadministered to the subject. However, it should be understood that theantagonist could be administered shortly after the administration of theagonist or otherwise, the agonist could be administered shortly afterthe administration of the antagonist. It is important, however, in thecontext of this mode of treatment that there is a generally similartherapeutic amount of the antagonist along with the agonist. In thisway, the user will not suffer a severe withdrawal symptom which wouldotherwise occur with the presense of a large amount of the antagonistand a very small amount of the agonist. In like manner, the user willnot be able to obtain the pharmacologic effects to which he or she wasnormally accustomed if there is not an excess of the agonist without acorresponding presence of a substantial amount of the antagonist.

Any means for delivering the agonist and the antagonist may be employed.For example, the agonist and the antagonist may be administered by meansof a transdermal patch, as hereinafter described or it may beadministered by means of a pill or tablet, or the like. Moreover, theagonist and an antagonist could be administered intravenously or byother means known for administration of medicaments e.g. sublingually,etc.

The preferred modes of administering the agonist or the antagonist andpreferably both relies upon the use of a transdermal patch P of the typeillustrated in FIG. 1 of the drawings. This patch P is adapted forapplication to a suitable portion of a smoker's body, as for example, ona forearm or a chest of the individual or the like.

The patch P comprises a lower liquid permeable membrane or layer 10along with a suitable non-permeable covering or outer enclosing layer 12and which forms a reservoir 14 therebetween. This reservoir 14 is sizedto receive an agonist or an antagonist or both and which usually may beprovided in a liquid form. The layer 10 may be provided on its undersurface with an adhesive layer 16 covered by a releasable backing 18.Thus, when the releasable backing 18 is removed, the patch P can beadhered to the skin of a user through the adhesive layer 16. Theadhesive layer 16 is also sufficiently porous so that any agonist orantagonist contained within the reservoir 14 may be transdermallyapplied to the user. In like manner, and for this purpose, smallapertures could be formed within the adhesive layer 16, if desired.

The membrane 10 and the outer enclosing layer 12 may be formed of acotton material or similar cloth-like material which is capable ofretaining, but yet permitting dispensing of the agonist and antagonistor a liquid carrier which would hold the agonist and the antagonist. Forthis purpose, both the agonist and the antagonist may be liquid, orotherwise dissolved in a liquid carrier. The patch P may also beprovided in the reservoir 14 with a silicone polymer matrix comprised ofa cross-linked rubber and having micro-sealed compartments which areeffectively formed by the cross-linking of the silicone rubber.

The exact details of construction of the patch P are not critical withrespect to the present invention and other forms of dermally applicablepatches can be used. One such patch is illustrated, for example, in U.S.Pat. No. 3,797,494 to Zaffaroni. Other patches which can be used areillustrated in U.S. Pat. No. 3,731,683 to Zaffaroni and U.S. Pat. No.4,336,243 to Sanvordeker et al.

The patch P preferably has a size of about two centimeters by twocentimeters at a minimum. Preferably, the patch has a surface area ofabout five centimeters by five centimeters with a thickness of about twoto three millimeters. There is no effective outer limit on the size ofthe patch, except for convenience. When administering nicotine as thedrug, the nicotine may be present in an amount so as to provide thatamount of nicotine which would be acquired by a smoker. As a simpleexample, a patch could deliver a few milligrams of nicotine per hour.For a 24-hour delivery period the patch would have a size and thicknessto retain about a minimum of 50 milligrams of nicotine.

In one of the preferred embodiments, when utilizing a transdermal patch,nicotine should be available so as to provide one to four milligrams perhour. The smoker normally obtains about two to about four milligrams perhour of nicotine as a result of a normal smoking pattern. Thus, at leastthe amount of nicotine to which the smoker is accustomed is generallypresent. The mecamylamine is present in an amount of 0.5 milligrams toabout one milligram per hour delivery. These relative amounts of thenicotine and the mecamylamine are present at the start of any nicotinereduction program and may be reduced after a period of time. After aperiod of time, the nicotine is reduced to no more than one milligram ofnicotine to be delivered per hour along with about 0.5 milligrams ofmecamylamine.

The patch has been found to be highly effective in that it provides asteady rate of delivery of both the agonist and the antagonist. In thisway, there are no excessive levels of either, as previously described.Oral time release capsules can also provide the same effect. However,better control is provided when using the transdermal patch. An oralspray such as an aerosol spray can be used to administer the nicotineand the mecamylamine or for that matter, the other agonists andantagonists. However, the delivery of nicotine through an oral spraycould present a problem due to the harshness and the severe irritationwhich results in the respiratory tract when inhaled, although this maybe mitigated by mecamylamine.

The patch described herein can be placed on any convenient area of theusers skin, such as, the underside of the forearm of the user's body oron the chest of an individual. In this way, when the patch is applied tothe user's body it will release a continuous supply of nicotine to thesmoker.

The nicotine and/or the mecamylamine may be dissolved in an inertvehicle, such as, for example, K-Y jelly or any other liquid carrierwhich does not react with the body or with the nicotine or the otheragonists and the mecamylamine and other antagonists. The vehicle mustalso readily permit transdermal migration of the nicotine andmecamylamine. One of the primary liquid carriers which may be used iswater. However, various low molecular weight alcohols, such as ethanol,etc. could be used. In addition, glycerol, propylene glycol, petrolatum,etc. are effective carriers for the nicotine and mecamylamine.

The nicotine and mecamylamine are each added to the liquid carrier in anamount of about 3 percent by weight to about 10 percent by weight,particularly when water is the liquid carrier. In this case the amountof the two components added to the carrier are limited by the solubilityof the mecamylamine. The amount of nicotine and mecamylamine to be addedto the carrier is a function primarily of the desired rate of delivery,as hereinafter described, and is, in turn, a function of e.g. patchsize, pH of the carrier, etc.

The carrier preferably should have a pH of no higher than about eight ornine, although it can be made less basic or more acidic, as hereinafterdescribed, in order to control nicotine penetration rates. Nicotine iswell known to penetrate the intact skin, particularly at a pH of aboutseven or greater.

The amount of any agonist and any antagonist introduced into a liquidcarrier is a function of the solubility of the components in the carrieras well as the desired rate of delivery. Moreover, patch construction tosome extent will affect the rate of delivery.

The relative amounts of agonist and antagonist which are administered toa subject are functions their receptor occupancy. Thus, it is desirableto provide the relative amounts of agonist and antagonist which presentan equivalent amount of binding at the brain receptors for the agonist.

It is also possible to add to the liquid carrier an agent to increasethe permeability of the skin, such as dimethyl sulfoxide (DMSO) orequivalent agent. The dimethyl sulfoxide is a topical agent whichfacilitates penetration of the agonsit through the skin. Other similaracting agents which can be used include, e.g. sodium lauryl sulfate,1-dodecylhexahydro-2H-azepin-2-one (Azone) and a mixture of propyleneglycol and oleic acid.

The patch P has been found to be effective in administering either theantagonist or the agonist and preferably both in this embodiment of theinvention. The patch is preferable inasmuch as it may provide acontrolled rate of delivery of the agonist and antagonist to the userand also maintain a sustained level of the agonist and antagonist in theusers bloodstream. By controlling the membrane size and like factors, itis possible to regulate the rate of delivery of these ingredients to theuser. Moreover, the patch provides the desired pharmacologic effects towhich the user is accustomed, but still blocks the need for theadditional external administration of the drug. It also enables adisassociation of the convenient means for delivery of the drug. Aperson addicted to nicotine is accustomed to smoking as a means toderive that nicotine. When the patch is employed, there is no longer areinforcement of the need for smoking to obtain the desired level ofnicotine. In the case of a heroin addict who utilizes an intravenousneedle, there is a disassociation in that the intravenous mode ofadministration is no longer required.

The second approach for treatment of drug dependencies utilizing theagonist and antagonist combinations relies upon an inverse conditioningfor smoking cessation. This approach differs from the previouslydescribed approach in that the aim of the first approach is to saturatethe nicotine receptors to thereby insulate the user from the reinforcedeffects of taking a drug. In this latter approach, the inventioncounter-conditions the stimuli associated with the administration ofthat drug by reversing the usual consequences of taking the drug.

In one of the preferred embodiments of the invention utilizing thislatter approach of counter-conditioning, the drug or the agonist isapplied to the individual in a level which would approximate thatpreviously obtained by the individual. For example, the addict of heroinor morphine would receive methadone as the agonist to heroin or themorphine since methadone has a more constant systemic level. Themethadone would be administered in amounts which would approximate thepharmacologic effects to which the individual was previously accustomedif the antagonist were not administered. In like manner, the partyaddicted to nicotine would receive that general level of nicotine towhich he or she was previously accustomed. The administration of thenicotine or the other drug would preferably occur by any convenientmeans which was different than the addicted patients usual form ofadministration. Thus, the morphine or heroin could be taken through theoral cavity if the subject previously used intravenous delivery. Thenicotine would preferably be applied by means of a transdermal patch.When a desired amount of the agonist has been assimilated into thesystem of the user, the user is then provided with a means foradministration of the antagonist which would simulate the methodpreviously used for taking the abused drug. In this case, for example,the user would be provided with naltrexone or otherwise naloxone inhypodermic needles, if in the past, the user had been accustomed toself-administering the morphine or heroin intravenously. Thus, thenaltrexone would also be administered intravenously. It can beappreciated that when the user formerly administered a substance, he orshe received a certain desired sensation. In this case, when thenaltrexone is administered, there is an inverse conditioning in thatthere would be an unpleasant effect of withdrawal. The more that theuser attempted to reinforce his or her habit by using intravenousneedles, there would be a greater withdrawal. As a result, there is aninverse conditioning.

The same holds true in the case of the party addicted to nicotine. Theact of smoking would then be negatively correlated with nicotineeffects. The typical smoker is accustomed to receiving a nicotinereinforcement or so-called "high" by drawing puffs of smoke from acigarette, a pipe, or other means for burning tobacco. In this case, thesmoker is administered nicotine chronically through a transdermal patchor equivalent method of delivery other than by smoking. The smoker wouldalso be provided with an artificial cigarette or other smoking devicewhich contains mecamylamine as opposed to nicotine. In this case, theusual conditioning associated with smoking, namely increased nicotinestimulation and the pleasurable effects derived therefrom would not beobtained. In fact, there would be a withdrawal and in this paradigm,smoking would be associated with decreased nicotinic stimulation and theunpleasant effects of withdrawal. Thus, whenever the user smoked theartifical cigarette or similar smoking device, the user would beprovided with the full range of sensory and motor aspects of smokingassociated not with an increase, but rather a decrease innicotine-induced satisfaction. The satisfaction provided by the systemiclevel of nicotine would be lessened by each bolus of mecamylamine thatis inhaled.

FIGS. 6 and 7 clearly show this effect of inverse conditioning. Byreference to FIG. 6, the normal nicotine receptor activation orsatisfaction is shown on a scale as a function of time. Each puff of acigarette or similar smoking device provides a certain level ofsatisfaction since each puff of the tobacco smoke provides thesatisfying drug, nicotine. In the inverse conditioning as shown in FIG.7, it can be observed that there is an elevated base line of nicotine inthe subject's bloodstream. Thus, the subject is "pre-loaded" withnicotine from the transdermal patch. However, on each occasion when apuff of the artificial cigarette is taken, there is a decrease in theamount of the satisfaction obtained. Thus, in comparison, whereas anincrease in satisfaction occurred with each puff, in FIG. 6, a decreasein the satisfaction results with each puff, as shown in FIG. 7.

Those artificial smoking devices which are illustrated and described inthe aforementioned patent application (now U.S. Pat. No. 4,846,199)could be used for the purposes of administering the antagonist inaccordance with this embodiment of the invention. One such smokingdevice is illustrated in FIG. 2 of the drawings and comprises an outerhousing 20 which may adopt the size and shape of a conventionalcigarette. Thus the housing 20 is elongate and cylindrically shaped.Located within the housing 20 is a concentrically disposed,diametrically reduced cylindrically shaped divider 22 which forms anignitable fluid chamber 24 containing a suitable ignitable fluid, suchas a conventional lighter fluid e.g. liquid propane, butane, or thelike. Any conventional petroleum distillate, such as conventionallighter fluids, may be employed for this purposed.

A pair of intermediate discs or walls 26 and 28 are located within thehousing 20. Concentrically disposed within the divider tube 22 is anelongate smoke delivery tube 30. Mounted on the right hand end of thesmoke delivery tube 30, reference being made to FIG. 2 is a filter 32 tocreate a draw or inhalation resistance, such as in a conventionalcigarette filter. Located at the opposite end of the smoke delivery tube30 is an enlarged ampule or reservoir 34 containing the antagonist,mecamylamine. The ampule 34 may be formed of glass or graphite or otherinert material.

Extending from the chamber 24 containing the ignitable fluid is a wick36 having an end 38 capable of being ignited to create a flame. However,by reference to FIG. 2, it can be observed that the ampule 34 is locatedin a position where it is not immediately above the flame of theburnable end 38 and therefore is not heated. When the smoker desires tocreate an aerosol of the constituents in the ampule 34, the smokedelivery tube 30 and hence the ampule 34 are shifted to the left,reference being made to FIG. 2. The constituents in the ampule 34 willbecome heated and form an aerosol.

The ampule 34 may be provided with an air inlet opening 40 so that whena suction is imparted to the ampule 34, through the smoke delivery tube30, the aerosol will travel through the smoke delivery tube 30 andthrough the filter 32. A similar opening 42 may be formed in the endwall of the housing 20 for this purpose. The air inlet opening 42 alsooperates as a vent to prevent excessive pressure build-up within theampule 34.

Thus, when the smoker desires to inhale, an aerosolized amount of acharge of the mecamylamine will be generated and inhaled, providing thenegative effects described above. The user merely pushes on the smokedelivery tube 30 so that the ampule 34 is located over the flame of theburnable end 38 and within a matter of a few seconds, a sufficientamount of aerosol has formed, equivalent to that which would begenerated in a puff by the smoker on a normal cigarette. This aerosolcould even be visually similar to normal cigarette smoke. It could alsobe incorporated with agents to provide a similar aroma and other sensoryqualities resembling cigarette smoke.

A spring 44 is disposed between the right-hand end wall 26 in the outerhousing 20 and the filter 32. Moreover, an outer cover sleeve 46 isdisposed over the spring between the filter 32 and the housing 20. Thehousing 20, as well as the sleeve 46, may both be formed of a suitablepaperboard material which is relatively inexpensive so that the entireapparatus functions as a disposable cigarette which may be disposed ofwhen the charge of antagonist in the ampule 34 has been depleted.Otherwise, the entire apparatus of FIG. 2 could be constructed to bereusable with the ampule capable of being recharged.

It is possible to generate the aerosol at a relatively low temperatureby boiling the liquid antagonist solution, namely mecamylamine solution.For example, temperatures as low as 200 degrees C. could be used forgenerating a vapor and hence an aerosol of the condensate. Consequently,there is no significant combustion and hence poisonous products ofcombustion. Alternatively, a nebulizer such as an ultrasonic nebulizercould be used to create the aerosol to thereby eliminate any heating ofthe contents of the ampule.

FIG. 3 illustrates a modified form of an apparatus for smoking of anantagonist, such as mecamylamine, and which comprises a conventionalfilter tipped cigarette 50 comprised of a paper tube 52 filled withground tobacco 54. A conventional filter 56 is provided at theright-hand end of the cigarette in a conventional manner. The presentinvention provides an elongate tube 58 extending concentrically withinthe cigarette from one end thereof to the other and which is opened ateach of the opposite ends. The tube 58 may also be formed of a papermaterial or similar burnable substance.

The tube 58 is provided on its interior with an antagonist such asmecamylamine. In this case, the antagonist could be in the form of aheavy gel which is coated on the interior surface of the tube 58. Theburning cigarette 50 will provide the source of heat which willvolatilize the mecamylamine. thus, as the left-hand end of the cigaretteis ignited, the heat from the burning end of the cigarette willvolatilize the mecamylamine enabling the mecamylamine to be inhaled bythe smoker upon puffing at the filter 56.

In accordance with the construction illustrated in FIG. 3, it can beobserved that there is very little draw resistance through the tube 58.Approximately 90 percent of any intake of the aerosol or smoke will bethrough the tube 58. While any drawing of air through the burning end ofthe cigarette will indeed produce cigarette smoke, this will be in arelatively small quantity. Nevertheless, this embodiment of theinvention is effective in that it will provide some nicotine to the userso that there may not be a complete withdrawal syndrome. Thus, thedevice could be constructed so that the amount of nicotine which isgenerated can be proportioned to the amount of the antagonist,mecamylamine. In this way, it is possible to tailor the device to theparticular needs of an individual in which smoking cessation is desired.This type of smoking apparatus is also effective in that it will havethe feel and appearance of a conventional cigarette and will also enablethe smoker to receive unaltered cigarette smoke along with theantagonist. If the amount of the antagonist is substantially greaterthan the amount of cigarette smoke, there still will be a net effect ofa withdrawal. This further reinforces the decrease in nicotine-inducedsatisfaction.

FIGS. 4 and 5 illustrate another modified form of smoking device 60 andwhich is very similar in construction to the smoking device 50 of FIG. 3in that it employs a conventional filter tip cigarette. In thisembodiment, the elongate smoke delivery tube 58 is provided on itsinterior surface with a plurality of radially inwardly extendingsomewhat flexible fingers 62. These fingers may actually adopt the formof filaments and are sufficiently flexible so as to yield to the draw ofaerosol through the delivery tube 58. The fingers 62 generally extendrandomly throughout the annular interior surface of the delivery tube 58and are effective to preclude any of the liquid antagonist from rollingout of the delivery tube 58 when the cigarette is held in a verticalposition with the outer end located downwardly. Thus, the liquidantagonist will collect in the spaces 64 between the point of connectionof the fingers 62 and the interior surface of the wall of the tube 58.

It can be observed that the smoking device 60 is also effective ingenerating an aerosol or smoke of the antagonist similar to the devicein FIG. 3. Thus, this device would also be effective in increasing thenegative effect associated with the smoking of a cigarette.

It can be observed in connection with this approach for reducing thedependence on drugs, and in particular nicotine, that there is aninverse conditioning to tobacco smoke whereby the act of smoking isnegatively correlated with nicotine effects. The smoker is givennicotine through the patch or other means as aforesaid and themecamylamine is obtained through an artificial cigarette which maysimulate the appearance, size and shape of a conventional cigarette. Asindicated above, this smoking would be associated with decreasednicotine stimulation and the unpleasant effects of withdrawal. As longas the subject did not resume tobacco smoking as through conventionalcigarettes, this inverse conditioning would lessen the temptationprovided by smoke from external sources, as for example from thirdparties cigarettes.

In the case of cocaine, amphetamines and other stimulants, an agonistsuch as bromocriptine could be used. The bromocryptine would typicallybe administered in an amount of about 40 to 100 milligrams per day.Again, this agonist could be taken orally or otherwise by means of atransdermal patch. However, with a transdermal patch, the bromocriptineagonist would typically be administered in a rate of about 10 to 25milligrams per day. The antagonist for cocaine, amphetamines and theseother stimulants would be fluphenazine such as fluphenazinehydrochloride. This fluphenazine hydrochloride would be taken at a rateof about 20 to 60 milligrams per day orally. In like manner,fluphenazine decanoate could also be used as an antagonist at a rate ofabout 25 to 75 milligrams in each three week period. This latterantagonist would be injected intramuscularly.

With respect to heroin and other opiates, the agonist is methadone andwould normally be administered orally in an amount of about 30 to about120 milligrams per day. The antagonist for the opiates is naltrexone, asaforesaid. The naltrexone would be administered in a rate of about 40 toabout 70 milligrams per day. Again, the naltrexone could be administeredorally or intravenously, although it is preferably administeredintravenously to negatively correlate to the effects of the abused drug.It should be understood that other drug dependencies with drugs such asbarbituates, benzodiazopines and alcohol could also be treated with thiscombination of agonist and antagonist treatment. Dangerous withdrawalsymptoms would still be carefully monitored and controlled.

The invention is also effective in therapeutically treatingpsychophysiological diseases and disorders involving neuronaldysregulation and which may also involve a drug use. As indicatedpreviously, psychiatric disorders which involve the dysregulation of aneurotransmitter including manic depression and schizophrenia could betreated by the method of the present invention. In this case, fortreatment of psychiatric dysorders of this type, bromocriptine would beused as an agonist, generally in the amounts used for treatment ofcocaine. The fluphenazine, or the other derivitives thereof, would beused as the antagonist, also in the ranges as indicated above.

Diseases involving the imbalances of the autonomic nervous system canalso be treated by this agonist-antagonist drug administration.Sympathetic nervous system disorders, such as hypertension, could alsobe treated with administration of adrenergic agonists and antagonists.Parasympathetic nervous system disorders could also be treated withconcurrent treatment of muscarinic cholonergic agonists and antagonists.

The present invention also provides a unique composition of the agonistand the antagonist as indicated above. This agonist and antagonistcombination is effective and unique in that it would not be expected toprovide the beneficial results described herein. One would assume thatthe agonist and antagonist would counter the effects of each otherthereby providing essentially no effect whatsoever. However, it has beendetermined in accordance with the present invention that thiscombination of agonist and antagonist is highly beneficial as previouslydescribed. It is important to provide a composition to the user so thatthe user may not discard the antagonist and only resort back to the oldhabit of using the agonist. This is particularly true with the highlyaddictive drugs such as the opiates and the like. Thus, the compositionof the invention is an important contribution to the practice of themethod and is highly effective therefore.

EXAMPLES

The invention is further illustrated by but not limited to the followingexamples.

Example 1

Approximately three milligrams per hour of nicotine is administered to asubject having a nicotine dependency. The nicotine is administered bymeans of a transdermal patch applied to the forearm of the subject.Mecamylamine is also administered simultaneously through the same patchat a rate of 15 to 30 milligrams per day. It is found that this type ofadministration substantially occupies the receptors in the brain of thesubject thereby reducing the desire for nicotine intake.

Example 2

In example 2 a subject having nicotine dependency is treated byadministration of the agonist-antagonist combination in accordance withthe present invention. In this case, the nicotine is administered to asubject through a transdermal patch such that there is about 20nanograms of nicotine in each milliliter of the person's bloodstream atany point in time.

The subject is provided with a simulated cigarette or so-calledartificial cigarette, similar to that illustrated in FIG. 3 of thedrawings. The ampule of that artificial cigarette is provided withmecamylamine. When the user draws upon the filter of the cigarette, hereceives a charge of mecamylamine which causes a withdrawal effect.This, in turn, inversely conditions the smoker and ultimately causes thesmoker to associate negative feelings with smoking of cigarettes therebyreducing the tendency of the smoker to resort to a smoking habit.

Example 3

A subject having a heroin addiction is treated by cessation of allheroin administration. The subject is provided with about 70 milligramsper day of methadone and which is administered orally. Simultaneously,the subject is also provided with naltrexone administered at a rate ofabout 50 milligrams per day and which is administered orally.

The brain receptors for these opiates are substantially filled therebyreducing the desire of the subject for further intake of heroin or anagonist thereof.

Thus, there has been illustrated and described a unique and novelcombination of an agonist and an antagonist for treatment of drugdependency and other psychophysiological diseases and disorders. Thepresent invention thereby fulfills all of the objects and advantageswhich have been sought therefore. It should be understood that manychanges, modifications, variations and other uses and applications willbecome apparent to those skilled in the art after considering thisspecification and the accompanying drawings. Therefore, any and all suchchanges, modifications, variations and other uses and applications whichdo not depart from the spirit and scope of the invention are deemed tobe covered by the invention.

Having thus described our invention, what we desire to claim and secureby letters patent is:
 1. A pharmacologic composition for the treatmentand reduction of dependency on an abused drug which results inactivation of nicotine receptors, said composition comprising:a) a drugacting upon nicotine receptors and which causes activation of thosenicotine receptors, said drug being present in the composition in anamount which at least partially satiates the needs for the abused drugby a subject using the composition; b) an antagonist to the drug whichis effective to reduce the effects of the drug activating thesereceptors and present in the composition in an amount sufficient to atleast partially block the activation of those receptors by the drug, theantagonist being selected so that these same receptors responsive to thedrug are also sensitive to the antagonist, the relative amount of thedrug and the antagonist being present in the composition so that thereis a substantial systemic amount of the antagonist present when there isa substantial systemic amount of the drug present in the blood of asubject using the composition, the drug or agonist of the drug causingthe receptors to be activated and the antagonist causing additionalreceptors to be blocked, the drug and the antagonist being administeredin the proper amounts to preclude intoxication or overdosing and to alsoreduce pleasure achieved by a subject when the abused drug isadministered and to also reduce a state of withdrawal from the abuseddrug in the subject, such that the drug is complemented by theantagonist to occupy a greater number of receptors of the subject thanwould be occupied by the drug alone and with the drug and the antagonisthaving opposing effects on stimulation of the receptors and leaving alessor number of receptors available to respond to an abused drug. 2.The composition of claim 1 further characterized in that the drug andthe antagonist are administered contemporaneously.
 3. The composition ofclaim 1 further characterized in that the drug is nicotine.
 4. Apharmacologic composition for the treatment and reduction of drugdependency and psychophysiologic and psychologic disorders and diseasesin a subject by reducing over-activity or under-activity of receptorsresponsive to nicotine, and where any drug of dependency or the diseaseor disorder activates those receptors responsive to nicotine, saidcomposition comprising:a) a drug or an agonist of that drug present inthe composition in an amount which acts on the nicotine receptors of thesubject to thereby activate those receptors and at least partiallysatiate the needs for the drug by the subject using the composition; b)an antagonist to the drug or agonist present in the composition in anamount sufficient to at least partially block the activation of thesereceptors by the drug and thereby reduce the systemic effects of thedrug or agonist, the amount of the drug or agonist and the amount of theantagonist being present in the composition so that there is always asubstantial systemic amount of the antagonist present when there is asubstantial systemic amount of the drug or agonist present in the bloodof a subject using the composition, the drug or agonist and theantagonist being present in the composition to be administered in theamount to preclude intoxication and to also reduce any pleasure achievedby a subject to whom administered and to also prevent a state ofwithdrawal from the drug or agonist in the subject, to thereby reduceover-activity and under-activity in the receptors responsive to nicotinecaused by administration of a drug or agonist or withdrawal from thedrug or agonist, the amount of the drug or agonist and the antagonistalso being established so that the drug or agonist is complemented bythe antagonist to occupy a number of nicotine receptors of the subjectusing the drug or agonist which is greater than the number of nicotinereceptors which would be occupied by the drug or agonist alone and withthe drug or agonist and the antagonist having opposing effects onstimulation of the receptors and leaving a lesser number of receptorsavailable to respond to an abused drug, at least one of the drug oragonist being provided in a form so as to be administered by a techniqueother than that to which the subject using the composition wasaccustomed to administering the drug.
 5. The composition of claim 1further characterized in that the drug or its agonist and the antagonistare administered contemporaneously.
 6. A pharmacologic composition forthe treatment of physiological and psychophysiological dysfunction of asubject in which the activity of receptors responsive to nicotine are instates of over-activity or under-activity and where the compositionreduces this over-activity and under-activity, said compositioncomprising a drug or an agonist of that drug present in the compositionin an amount which would prevent under-activity of the nicotinereceptors causing the physiological or psychophysiological dysfunctionand where the receptors responsive to nicotine are also responsive tothe drug or the agonist, and an antagonist to the drug or agonistpresent in the composition and where the receptors responsive tonicotine are also sensitive to the antagonist, said antagonist alsobeing present in an amount sufficient to prevent over-activity of thenicotine receptors and at least partially block the pharmacologiceffects of the drug or agonist and also reduce over-activity of thenicotine receptors, the amount of the drug or its agonist and the amountof the antagonist being present in the composition so that there isalways a substantial systemic amount of the antagonist present whenthere is a substantial systemic amount of the drug or agonist present inthe blood of a subject using the composition, the drug or agonist andthe antagonist being administered in amounts to preclude intoxicationand to also prevent under-activity of receptors causing the physiologicor psychophysiologic dysfunction, such that the drug or agonist iscomplemented by the antagonist to occupy a number of receptors of thesubject using the drug or agonist which is greater than the number ofreceptors which would be occupied by the drug or agonist alone, and theantagonist having opposing effects on stimulation of the receptors andleaving a lesser number of receptors available to respond to the drug oragonist.
 7. The composition of claim 6 further characterized in that thedrug or its agonist and the antagonist are administeredcontemporaneously.
 8. A composition for therapeutically treatingphysiological and psychophysiological activities of a subject whichresults from over-activity or under-activity of receptors of the subjectresponsive to nicotine and where variations in amounts of an endogenoussubstance of the subject produce the over-activity and under-activity ofthe receptors responsive to nicotine; said composition comprising afirst component comprising a drug or an agonist of the drug which ifadministered in absence of an antagonist to the drug would cause asubstantial increase of the physiological or psychophysiologicalactivity and a second component comprised of an antagonist which ifadministered in absence of the drug or agonist, would cause asubstantial decrease in the physiological or psychophysiologicalactivity, the amounts of the agonist and antagonist present in thecomposition being established so that a substantial portion of thereceptors of nicotine are occupied by the agonist or antagonistsufficient to reduce the over-activity and under-activity of thereceptors to a desired level, and the drug or agonist and the antagonistbeing packed for generally contemporaneous administration to a subject.9. The composition of claim 8 further characterized in that the agonistor drug is present in the composition in an amount so that a substantialamount of the nicotine receptors are saturated with the drug or agonist,and the antagonist also being present in an amount so that theover-activity and under-activity of the subject which result fromactivation of the nicotine receptors is reduced.
 10. A pharmacologiccomposition for the treatment and reduction of dependency on an abuseddrug which results in the activation of nicotine receptors, saidcomposition comprising:a) a drug acting upon nicotine receptors whichcauses activation of those nicotine receptors, said drug being presentin the composition in an amount which provides a desired pharmacologiceffect to substantially the same extent as the effect produced by anamount of nicotine sufficient to at least partially satiate a need forthe nicotine and which thereby at least partially satiates the needs forthe abused drug by a subject using the composition; b) an antagonist tothe nicotine receptor activating drug which is effective to reduce theeffects of the drug activating these receptors and present in thecomposition in an amount sufficient to at least partially blockactivation of these receptors by the drug to substantially the sameextent as the effect produced by an amount of mecamylamine which wouldblock the effects of the drug or agonist, the antagonist being selectedso that these same receptors are responsive to the drug are alsosensitive to the antagonist, the relative amount of the drug and theantagonist being present in the composition so that there is asubstantial systemic amount of the antagonist present when there is asubstantial systemic amount of the drug present in the blood of asubject using the composition, the drug or agonist causing the receptorsto be activated and the antagonist causing similar receptors to beblocked, the drug and the antagonist being administered in the properamounts to preclude intoxication or overdosing and to also reducepleasure achieved by a subject when the abused drug is administered andto also reduce a state of withdrawal from the abused drug in thesubject, such that the drug is complemented by the antagonist to occupya greater number of receptors of the subject than would be occupied bythe drug alone and with the drug and the antagonist having opposingeffects on stimulation of the receptors and leaving a lesser number ofreceptors available to respond to an abused drug.
 11. The composition ofclaim 10 further characterized in that the nicotine receptor activatingdrug and the antagonist are administered contemporaneously.
 12. Thecomposition of claim 10 further characterized in that the drug actingupon nicotine receptors is also nicotine.
 13. A pharmacologiccomposition for the treatment and reduction of drug dependency andpsychophysiologic and psychologic disorders and diseases in a subject byreducing over-activity or under-activity of receptors responsive tonicotine and where the drug of dependency or the disease or disorderactivates these receptors responsive to nicotine, said compositioncomprising:a) a drug or an agonist of that drug present in thecomposition in an amount which acts on the nicotine receptors of thesubject to thereby activate these receptors and at least partiallysatiate the needs for the drug by the subject using the composition andalso in an amount to provide pharmacologic effects to substantially thesame extent as the effect produced by an amount of nicotine sufficientto at least partially satiate a need for nicotine; b) an antagonist tothe drug or agonist present in the composition in an amount sufficientto at least partially block the activation of these receptors by thedrug to substantially the same extent as the effect produced by anamount of mecamylamine sufficient to block the effect of the drug oragonist and thereby reduce the systemic effects of the drug or agonist,the amount of the drug or agonist and the amount of the antagonist beingpresent in the composition so that there is always a substantialsystemic amount of the antagonist present when there is a substantialsystemic amount of the drug or agonist present in the blood of a subjectusing the composition, the drug or agonist and the antagonist beingpresent in the composition to be administered in the amount to precludeintoxication and to also reduce any pleasure achieved by a subject towhom administered and to also prevent a state of withdrawal from thedrug or agonist in the subject, to thereby reduce over-activity andunder-activity in the receptors responsive to nicotine caused byadministration of a drug or agonist or withdrawal from the drug oragonist, the amount of the drug or agonist and the antagonist also beingestablished so that the drug or agonist is complemented by theantagonist to occupy a number of nicotine receptors of the subject usingthe drug or agonist which is greater than the number of nicotinereceptors which would be occupied by the drug or agonist alone and withthe drug or agonist and the antagonist having opposing effects onstimulation of the receptors and leaving a lesser number of receptorsavailable to respond to an abused drug, at least one of the drug oragonist being provided in a form so as to be administered by a techniqueother than that to which the subject using the composition wasaccustomed to administering the drug.
 14. The composition of claim 13further characterized in that the drug or its agonist and the antagonistare administered contemporaneously.
 15. A pharmacologic composition forthe treatment of physiological and psychophysiological dysfunction of asubject in which the activity of receptors responsive to nicotine are instates of over-activity and under-activity, and where the compositionreduces said over-activity and under-activity, said compositioncomprising a drug or an agonist of that drug present in the compositionin an amount which would prevent under-activity of nicotine receptorscausing the physiological or psychophysiologic dysfunction tosubstantially the same effect as the effect produced by an amount ofnicotine sufficient to at least partially satiate a need for nicotine,and where the receptors responsive to nicotine are also responsive tothe drug or the agonist, and an antagonist to the drug or agonistpresent in the composition to substantially the same extent as theeffect produced by an amount of mecamylamine sufficient to block theeffect of the drug or agonist and where the receptors responsive tonicotine are also sensitive to the antagonist, said antagonist alsobeing present in an amount sufficient to prevent over-activity of thenicotine receptors and at least partially block the pharmacologiceffects of the drug or agonist and also reduce over-activity of thenicotine receptors, the amount of the drug or its agonist and the amountof the antagonist being present in the composition so that there isalways a substantial systemic amount of the antagonist present whenthere is a substantial systemic amount of the drug or agonist present inthe blood of a subject using the composition, the drug or agonist andthe antagonist being administered in amounts to preclude intoxicationand to also prevent under-activity of receptors causing the physiologicor psychophysiologic dysfunction, such that the drug or agonist iscomplemented by the antagonist to occupy a number of receptors of thesubject using the drug or agonist which is greater than the number ofreceptors which would be occupied by the drug or agonist alone, and theantagonist having opposing effects on stimulation of the receptors andleaving a lesser number of receptors available to respond to the drug oragonist.
 16. The composition of claim 15 further characterized in thatthe drug or its agonist and the antagonist are administeredcontemporaneously.
 17. A composition for therapeutically treatingphysiological and psychophysiological activities of a subject whichresults from over-activity or under-activity of receptors of the subjectresponsive to nicotine and where variations in amounts of an endogenoussubstance of the subject produce the over-activity or under-activity ofreceptors responsive to nicotine; said composition comprising a firstcomponent comprising a drug or an agonist of the drug and present in anamount so that the effect is substantially the same as the effectproduced by an amount of nicotine sufficient to at least partiallysatiate a need for nicotine, and which drug if administered in absenceof an antagonist to the drug would cause a substantial increase of thepsychological or psychophysiological activity and a second componentcomprised of an antagonist present in an amount so that the effect issubstantially the same as the effect produced by an amount ofmecamylamine sufficient to block the effect of the drug or agonist, asif the antagonist were administered in absence of the drug or agonistwould cause a substantial decrease in the physiological orpsychophysiological activity, the amounts of the agonist and antagonistpresent in the composition being established so that a substantialportion of the receptors of nicotine are occupied by the agonist orantagonist sufficient to reduce the over-activity or under-activity ofthe receptors to a desired level, and the drug or agonist and theantagonist being packed for generally contemporaneous administration toa subject.
 18. The composition of claim 17 further characterized in thatthe agonist or drug is present in the composition in an amount so that asubstantial amount of the nicotine receptors are saturated with the drugor agonist, and the antagonist also being present in an amount so thatthe over-activity and under-activity of the subject which result fromactivation of the nicotine receptors is reduced.